It is well documented that membrane excitability and excitation-contraction coupling are altered in the hypertrophied heart, and that ventricular hypertrophy is a risk factor for the development of life-threatening cardiac arrhythmias. Considerable evidence has accumulated to suggest that "electrical remodelling" occurs in the hypertrophied heart and that this reflects, at least in part, changes in the xpression and/or the properties of the voltage-gated K+ (Kv) currents that underlie myocardial action potential repolarization. The mechanisms involved in Kv channel remodeling in the hypertrophied ventricular myocardium, however, have not been delineated. The experiments proposed here will explore directly the molecular mechanisms underlying Kv channel remodeling in a mouse model of pressure overload-induced left ventricular hypertrophy (LVH). Regional differences in the effects of LVH on the functional expression, the properties and/or the distributions of ventricular Kv channels, particularly the transient outward K+ channels, I(to,f) will be determined, and experiments focused on delineating the roles of elevated intracellular Ca2+, Kv channel accessory subunits (KChIP2 and Kv-beta1) and the actin cytoskeleton in regulating functional I(to,f) channel expression will be completed. A sophisticated combination of electrophysiological, biochemical, molecular genetic, immunohistochemical and imaging techniques will be exploited in mice to achieve the stated aims of this proposal. We anticipate that the studies outlined here will provide fundamentally important new insights into the effects of pressure overload-induced left ventricular hypertrophy on repolarizing Kv channels, as well as into the molecular mechanisms underlying "electrical remodelling" in the hypertrophied heart.. In the long term, these insights should translate into more effective treatment strategies to reduce the risk of sudden death and the mortality and morbidity associated with myocardial hypertrophy and failure.